Abstract 984: Race- and ancestry-related metabolites and SNPs associated with response to secondary hormonal therapy in metastatic castration-resistant prostate cancer
Authors: Sean Alan Piwarski, Tyler Allen, Bonnie LaCroix, Lauren Howard, Morgan Paul, Nick Bachelder, Alex Sibley, Steve Patierno, Terry Hyslop, Kouros Owzar, Daniel George, Jennifer Freedman
Journal: Cancer Research (2023)

Abstract The number of new cases and deaths from prostate cancer (PCa) is highest for Black men compared with other racial and ethnic groups, and Black PCa patients have a shorter average survival as well as a greater risk of tumor recurrence than men of other racial and ethnic groups. However, recent studies have shown that Black PCa patients have a better response to certain therapeutic regimens than White PCa patients. This study focuses on addressing the critical need to determine novel relationships between ancestry-related genetic variation and PCa aggressiveness and response to secondary hormonal therapy in metastatic castration-resistant PCa (mCRPC). We conducted correlative science in a DoD Prostate Cancer Clinical Trials Consortium (PCCTC) prospective multicenter study of secondary hormonal therapy in mCRPC stratified by race, Abi Race. This study enrolled 50 self-reported Black and 50 self-reported White mCRPC patients, and such patients received abiraterone and prednisone until disease progression or adverse event. We performed metabolic profiling using serum samples from fasting patients at baseline and after treatment. In addition, we performed genome-wide genotyping using genomic DNA from whole blood specimens from patients at baseline. We then identified race- and ancestry-related metabolite and SNP variations that associated with outcome using a penalized Cox model approach. In addition, we used Ingenuity Pathway Analysis (IPA) and Lasso Analysis to further study race-related metabolites and SNPs. From these analyses, we identified sphingolipids such as ceramide as race-related metabolites associated with outcome as well as SNPs in Sphingosine Kinase Type 1-Interacting Protein (SKIP) associated with outcome. In addition, our analyses suggest that sphingolipids such as ceramides and SKIP may regulate cancer-related biofunctions differently in Black and White mCRPC patients undergoing abiraterone treatment. Both sphingolipids and SKIP are components of the Sphingosine Rheostat, the regulatory component of sphingolipid cellular metabolism often exploited by various cancers, in which ceramides displays a pro-apoptotic role whereas sphingosine-1-phosphate (S1P) is associated with an anti-apoptotic role and is indirectly regulated by SKIP via regulating the activity of Sphingosine Kinase (SPK1). Evaluation of the function of these sphingolipids and SKIP in PCa cell drug response and aggressiveness are currently underway. These findings are furthering understanding of race- and ancestry-related biological factors that influence response to secondary hormonal therapy in mCRPC and have the potential to impact selection of patients for secondary hormonal therapy and to mitigate PCa disparity. Citation Format: Sean Alan Piwarski, Tyler Allen, Bonnie LaCroix, Lauren Howard, Morgan Paul, Nick Bachelder, Alex Sibley, Steve Patierno, Terry Hyslop, Kouros Owzar, Daniel George, Jennifer Freedman. Race- and ancestry-related metabolites and SNPs associated with response to secondary hormonal therapy in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 984.